Aim of the PhD Project:
- Polysarcosine (pSar) is an emerging polypeptoid-stealth polymer emerging as an alternative to polyethyleneglycol (PEG).
- We will develop multimodal imaging tools (PET/optical) to:
- Understand the properties of pSar as a stealth polymer in nanomedicine
- Inform the development and clinical translation of novel nanomedicine-based drug delivery systems based on pSar.
Project Description / Background:
Polymers have been extensively and safely used in nanomedicine-based drug delivery systems (DDSs) for their ‘stealth’ properties. The main role of these stealth polymers is to allow DDSs to delay recognition by the reticuloendothelial system (RES) and prolong their circulation times. This in turn allows increases preferential accumulation of the DDSs in areas of disease, particularly in solid tumours (via the enhanced permeation and retention phenomenon) and areas of inflammation (e.g. rheumatoid arthritis, infection).
The most widely used stealth coating is based on polyethyleneglycol (PEG) polymers, having been used in several clinically-approved DDSs (e.g. Liposomal doxorubicin: Doxil/Caelyx). However, recent studies have shown that the use of PEG (that is present in many pharmaceutical products) results in anti-PEG immunity in humans (induced or pre-existing), resulting in faster RES recognition and hence accelerated blood clearance of PEG-containing pharmaceuticals. As a consequence, since the effectiveness of PEG-DDS rely on long circulation times, anti-PEG immunity has been suggested as one of the main reasons for the decreased therapeutic efficacy of DDSs in humans.
In the search of alternative stealth polymers with improved properties, the polypeptoid polysarcosine (pSar) has emerged as one of the most promising alternatives. pSar has shown stealth and safety properties in the preclinical setting, and benefits from potential advantages compared to PEG such as improved synthetic control leading to highly monodisperse polymers, and low immunogenicity. In addition, since it is not present in other pharmaceutic/cosmetic/household products, it is less likely to suffer by the presence pre-existing antibodies. Despite these advantages, there is a lack of detailed knowledge of the effect of pSar coatings in the short/long-term whole-body biodistribution (bioD) and pharmacokinetics (PK), and safety of DDSs.
In this project we will develop imaging tools to study the effects of pSar-coated DDSs systems based on star polymers . We will modify pSar-DDSs to allow in vivo and ex vivo multiscale and multimodal imaging using positron emission tomography (PET) and fluorescence imaging. This will allow us to investigate the effect of pSar coatings in several important aspects such as:
- What is the fate of DDS in vivo? What is the clearance route?
- What are the most relevant critical quality attributes (pSar length, DDS size, surface properties) for effective DDS tumour accumulation?
- What immune cells and molecules are implicated in the tumour uptake/clearance of DDSs? Do they induce an immune response?
- Are there gender-differences in the bioD/PK of pSar-DDSs?
- Do pSar DDS distribute in the bone marrow in a sufficient proportion to explore this carrier for therapeutic purposes?
We hope that by developing and integrating these imaging tools into the development of pSar-DDSs from the early stages, we will be able to efficiently inform their clinical translation and ultimately result in improved therapeutic options for patients. In addition, imaging pSar-DDSs may be used in a theranostic approach, by allowing indetification of patients that will truly benefit from pSar-DDSs treatment.
The student should have a background in at least one of these areas: radiochemistry, biomolecular sciences, biology/biological chemistry, pharmaceutical chemistry, drug delivery or molecular imaging.
- England et al, Biomacromolecules 2020, 21, 8,